One of the greatest hurdles in creating vaccines for a number of viral pathogens is the antigenic variability of viral coat proteins. The rapid mutation rate of a number of viruses (most notably influenza virus and HIV) allows the virus to escape the neutralizing antibody response induced by antiviral vaccines. The internal proteins of the virus, on the other hand, are generally highly conserved and have not evolved to rapidly alter their antigenicity. Antibody responses to these internal proteins, while a consistent feature of immune responses to viruses, almost always fail to influence viral infectivity, since the antibodies do not have access to their target antigens, which are located either inside the virus or inside the virus-infected cells. If, however, antibodies are introduced into the cytosol of cells, they do have the ability to prevent viral infection. Recent advances in understanding antibody folding indicate that antibodies can, under some circumstances, properly fold and bind antigen when they are expressed in the cytosol by removing their amino terminal ER insertion sequences. Therefore, cells or, eventually, transgeneic animals expressing such cytosolic antibodies should be resistant to virus infection. Using electroporation to introduce antibodies into the cytosol, we identified antibodies able to block infection of cells with influenza A or B viruses. Our ultimate goal is to clone the genes encoding these antibodies and to express them in the cytosol of tissue culture cells and, eventually, transgenic animals, thus creating animals resistant to influenza virus infection.